The goal of this proposal is to investigate the changes in the behavioral and metabolic phenotypes and neural correlates of obesity following the administration of two minor tobacco alkaloids as a novel approach to the prevention and treatment of obesity. The prevalence of overweight/obesity has increased to epidemic proportions and Veterans are more likely to become overweight. There are currently five FDA approved drugs on the market for the treatment of obesity, but their effects have been modest and their side effects undesirable. There is a crucial need to develop more effective pharmacotherapies to treat obesity in order to reduce morbidity/mortality of Veterans. Nicotine, the primary psychoactive and addictive component in cigarettes, has been shown to cause weight loss, and nicotine abstinence causes weight gain in human and animal studies. Cigarette smoking is undeniably unhealthy and the benefits of quitting smoking outweigh any positive effects smoking has on body weight. Even so, the ability of cigarette smoking to produce sustained weight loss and reduced food intake suggests that investigating the underlying mechanisms and studying similarly acting compounds may lead to novel anti-obesity drugs. In light of their similarities to nicotine, minor tobacco alkaloids (MTAs) are prime candidates for treating obesity. They are found in tobacco products at very low doses and act at nicotinic acetylcholine receptor subtypes, which are widely distributed throughout the brain and modulate the release of many neurotransmitters and neuropeptides involved in obesity. Specifically, nAChRs are located within the arcuate nucleus (AN), which plays a critical role in the drive to eat and within the ventral tegmental area (VTA) and nucleus accumbens (NAcc), which are involved in reward. However, few studies have actually examined MTAs and nAChR effects on ingestive behaviors. Considering the well-known ability of nicotine to affect ingestive behaviors, the lack of research on the minor tobacco alkaloid effects on food intake and weight gain represents a significant gap in the literature. Aim 1 will assess the extent to which the MTAs produce alterations in obesity phenotypes without affecting general malaise, anxiety or stress. Following peripheral administration of two minor tobacco alkaloids, nornicotine and anatabine, changes in food intake, body weight, energy expenditure, adiposity, and physical activity will be measured. To ensure that changes in these variables aren't due to the presence of malaise, anxiety, or stress, the MTAs will be evaluated with conditioned taste aversion and open field testing, and plasma corticosterone levels will be measured. Aim 2 will elucidate the neural mechanisms underlying the effects of the MTAs on obesity phenotypes by evaluating changes in neuronal activation following injections of the MTAs, specifically by quantifying cFos positive neurons within the AN, VTA, and NAcc, regions of the brain important for food intake and reward. Then, changes in body weight, food intake, adiposity, physical activity and energy expenditure following central administration of the MTAs into the AN in rats will be examined. The specific role of POMC neurons within the AN in mediating these effects will be assessed through the use of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in mice. Finally, Aim 3 will determine the therapeutic potential of the MTAs by providing rats with access to high fat diet (HFD) during peripheral MTA administration to assess the extent to which MTAs can prevent obesity, and assess MTA treatment efficacy after access to HFD for 12 weeks. We hypothesize that the MTAs will reduce weight gain, adiposity, and food intake and increase physical activity and energy expenditure through interactions with the neuropeptide POMC in the AN.